PROJECT SUMMARY ? THERAPEUTIC CORE The Therapeutic Core of the Johns Hopkins NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders (HAND) will play an integral role in the development of new therapeutic agents for HAND. The Therapeutic Core is operated by the Johns Hopkins Drug Discovery (JHDD) program, an integrated drug discovery team with extensive Pharma experience and capabilities in medicinal chemistry, assay development/screening, drug metabolism, pharmacokinetics, and animal pharmacology. Recent metabolomics studies profiling the cerebrospinal fluid (CSF) from cART-treated HIV patients showed increases in glutamate in patients with HAND compared to those without the symptoms. Other CSF biomarker studies showed an association between accumulation of sphingomyelin and ceramide and deficits in speed of information processing and working memory. These findings collectively provide the rationale for exploring glutamate homeostasis (Objective 1) and lipid metabolism (Objective 2) as mechanistic platforms to develop new HAND therapies with clinical relevance to CART treated HIV patients. In addition, our core will play a central role in providing HAND researchers with laboratory and consultancy services in drug discovery and development as well as engaging internal/external academic investigators and Pharma to evaluate new therapies being developed for other indications in HAND preclinical models (Objective 3). Working closely with the centers? Biomarker and Clinical cores, these activities should facilitate translational research towards developing novel therapeutics for HAND relevant to cART-treated patients.